The mesocorticolimbic dopamine (DA) system has been implicated in mediating the rewarding effects of various drugs of abuse. An involvement of this system in the development of drug-induced tolerance, withdrawal and sensitization, phenomenon which are thought to play a role in drug- craving and relapse, has more recently been postulated. Given the apparent involvement of mesolimbic neurons in the addiction process, ongoing studies are seeking to determine: i) whether manipulations which alter mesolimbic neuronal activity can alter the pharmacological and/or neurochemical effects of psychoactive drugs and ii) whether differences in the basal activity of this system or its responsivity to drugs of abuse underlie individual differences in compulsive drug-seeking behavior. Towards that end, classical (place preference conditioning) and operant (drug discrimination, self-administration) conditioning techniques, developed in the past year, are being used to characterize the rewarding effects of opioids and psychostimulants and to determine those pharmacological treatments which lead to or prevent sensitization. In-vivo microdialysis combined with HPLC and electrochemical detection is being used to quantitate dopamine and serotonin release/metabolism within the mesocorticolimbic system in response to various drugs of abuse and to various drug pretreatments. Identical studies in selected inbred rat strains are being initiated and the data generated will permit analysis of the neurochemical substrates underlying vulnerability to drug abuse.